Bystander suppression involves mucosal administration of antigens specific to a tissue under autoimmune attack.
Mucosal administration of certain antigens causes suppressor T-cells to be induced in mucosa-associated lymphoid tissue (MALT). These antigen-specific suppressor T-cells are released in the blood or lymphatic tissue and then migrate to the organ or tissue afflicted by the autoimmune disease (which has a high concentrated of the antigen). Once they have arrived at their intended target, these suppressor T-cells mediate the release of immunosuppressive cytokines such as transforming growth factor β (TGF-β), IL-4 and/or IL-10 and thereby suppress autoimmune attack of the afflicted organ or tissue.
In more detail, the mechanism of bystander suppression is as follows: After a tissue-specific bystander antigen is mucosally administered, it passes to local lymph tissue (such as Peyers Patches in the gut), which contain T cells and B cells. These cells, are in turn in communication with the immune system, including the spleen and lymph nodes. The result is that suppressor (CD8+) T-cells are induced and recruited to the area of autoimmune attack, where they cause the release of TGF-β, IL-4 and IL-10, which can non-specifically downregulate the B-cells as well as the activated CD4+T-cells directed against the mammal's own tissues. Despite the non-specific nature of the activity of these cytokines, the resulting tolerance is specific for the autoimmune disease by virtue of the fact that the antigen is specific for the tissue under attack and suppresses the immune cells that are found at or near the tissue being damaged.
TGF-B is an anti-inflammatory cytokine that helps polarize the immune response towards a Th2 phenotype. IL-4 and IL-10 are also antigen-nonspecific immunoregulatory cytokines. IL-4 in particular enhances Th2 response, i.e., acts on T-cell precursors and causes them to differentiate preferentially into Th2 cells at the expense of Th1 responses. IL-4 also indirectly inhibits Th1 exacerbation. IL-10 is a direct inhibitor of Th1 responses. After orally tolerizing mammals afflicted with autoimmune disease conditions with bystander antigens, increased levels of TGF-β, IL-4 and IL-10 are observed at the locus of autoimmune attack. Chen, Y. et al., Science, 265:1237-1240, 1994.
The action of these cytokines is not specific for the antigen triggering the suppressor cells that release them, even though these suppressor T-cells release these cytokines only when triggered by the mucosally-administered antigen. However, because mucosal tolerization with the antigen only causes the release of these cytokines in the vicinity of autoimmune attack, no systemic immunosuppression ensues. Recruitment of the suppressor T-cells to a locus where cells contributing to the autoimmune destruction are concentrated allows for the release of these suppressive cytokines in the vicinity of the disease-causing cells and suppresses (i.e. shuts down) these cells. The ability of these immunosuppressive cytokines to suppress these “destructive” cells is independent of the antigen for which the destructive cells may be specific.
U.S. Pat. No. 6,645,504 (“Weiner I”) and U.S. Pat. No. 5,935,577 (“Weiner II”) each discloses that certain synergists can be co-administered along with the antigen to enhance the effectiveness of the tolerance-promoting treatment. Particularly, noted is the use of IL-4; IL-10; bacterial lipopolysaccharides; immunoregulatory lipoproteins; and cholera toxin β-chain (CTB).